Submissions for variant NM_004168.4(SDHA):c.553C>T (p.Gln185Ter)

gnomAD frequency: 0.00001  dbSNP: rs775827529

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575535	SCV000664453	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	The p.Q185* pathogenic mutation (also known as c.553C>T), located in coding exon 5 of the SDHA gene, results from a C to T substitution at nucleotide position 553. This changes the amino acid from a glutamine to a stop codon within coding exon 5. In one study, this mutation was detected in tumor and normal tissue of a 31-year-old male patient whose gastrointestinal stromal tumor showed lack of SDHB and SDHA expression (Wagner AJ et al. Mod. Pathol. 2013 Feb;26:289-94). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000702668	SCV000831531	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln185*) in the SDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). This variant is present in population databases (rs775827529, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with a gastrointestinal stromal tumor (PMID: 22955521). ClinVar contains an entry for this variant (Variation ID: 480771). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Sema4, Sema4	RCV000575535	SCV002527754	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-16	criteria provided, single submitter	curation
GeneDx	RCV003159959	SCV003915015	pathogenic	not provided	2022-10-12	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22955521, 30877234, 26689913, 29625052)
Baylor Genetics	RCV003476321	SCV004200659	pathogenic	Dilated cardiomyopathy 1GG	2023-03-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003159959	SCV004562494	pathogenic	not provided	2023-09-06	criteria provided, single submitter	clinical testing	The SDHA c.553C>T; p.Gln185Ter variant (rs775827529) is reported in the literature in at least four individuals affected with either gastrointestinal stromal tumor (GIST), stomach adenocarcinoma, pancreatic cancer or paraganglioma (Ben Aim 2019, Lu 2015, Puccini 2022, Wagner 2013). This variant is also reported in ClinVar (Variation ID: 480771). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in individuals with GIST and are considered pathogenic (Pantaleo 2022). Based on available information, this variant is considered to be pathogenic. References: Ben Aim L et al. Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. J Med Genet. 2019 Aug;56(8):513-520. PMID: 30877234. Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015 Dec 22;6:10086. PMID: 26689913. Puccini A et al. Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients. Cancers (Basel). 2022 Sep 13;14(18):4447. PMID: 36139606. Wagner AJ et al. Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors. Mod Pathol. 2013 Feb;26(2):289-94. PMID: 22955521.